KRAS G12V mutation-selective requirement for ACSS2 in colorectal adenoma formation

Area of Science:

• Oncology
• Molecular Biology
• Cancer Metabolism

Background:

• Oncogenic KRAS mutations are common in colorectal cancer (CRC), associated with poor prognosis and treatment resistance.
• Specific KRAS mutations may lead to differential responses to therapies.
• Understanding KRAS mutation-specific effects is crucial for developing targeted treatments.

Purpose of the Study:

• To investigate the metabolic differences driven by common KRAS mutations in colorectal cancer.
• To identify mutation-specific vulnerabilities for targeted therapy.

Main Methods:

• Generation of isogenic Apc-null mouse colon epithelial cells with four common KRAS mutations.
• Transcriptomic and proteomic analyses to identify metabolic pathway alterations.
• Assessment of ACSS2 dependence and its role in tumor development and therapeutic response.

Main Results:

• KRAS G12V mutations enriched cholesterol and lipid metabolism pathways, mediated by SREBP1 and mTORC1.
• KRAS G12V cells showed increased ACSS2 expression and dependency for proliferation compared to other mutants.
• ACSS2 inhibition sensitized KRAS G12V cells to MEK inhibitors, revealing a specific vulnerability.
• ACSS2 was critical for KRAS G12V adenoma development but not KRAS G12D.

Conclusions:

• KRAS-driven CRC exhibits mutation-specific metabolic reprogramming.
• ACSS2 represents a potential therapeutic target, particularly in KRAS G12V-mutant colorectal cancer.
• Targeting ACSS2 may overcome therapeutic resistance in specific CRC subtypes.